Human beings alternate regularly between the states of sleep and wakefulness in a cycle that is normally in synchrony with the periodic rotation of the earth and with many geophysical phenomena such as the daily light-dark cycle. Sleep and wakefulness are normally consolidated into separate episodes with sleep occurring during the darkness at night and wakefulness occurring during the light of the day. Sleep, body temperature and plasma hormone concentrations and other constituents vary rhythmically in young adults living on a regular day-night schedule FIG. 1). Under normal conditions, these physiological rhythms, which have a variety of waveforms, have their own characteristic phase relationship with each other and with the twenty-four hour light-dark cycle.
In the absence of the periodic time cues of the external environment (e.g., sunrise and sunset), the cycle length or free-running period of daily oscillations of these rhythms is no longer synchronized or entrained to a twenty-four hour period. In humans, the free-running period is nearly always close to but not exactly equal to twenty-four hours. Hence the term circadian (circa=about, and dies=day) is used to describe these rhythms. In healthy young adult subjects, the average free-running period of the synchronized circadian system is longer than twenty-four hours. In other words, in the absence of periodic external cues, the internal biological clock runs a little slower than its mechanical or geophysical counterparts.
Under free-running conditions it is not only the sleep-wake cycle which remains periodic, but also many underlying physiological functions such as the core body temperature cycle and the secretion of melatonin from the pineal gland. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone that is normally secreted by the human pineal gland almost exclusively at night. One hypothesized function of the hormone melatonin is the transmission of information about the presence of light and dark to body tissues for temporal regulation of other body functions.
The suprachiasmatic nuclei, located in the hypothalamus of the human brain just above the optic chiasm, are believed to be the central neural pacemaker which coordinate inter-dependent circadian rhythms and synchronize their cycle length to periodic external cues FIGS. 2 and 3). In 1972 it was demonstrated that a pair of subcortical monosynaptic pathways, the retino-hypothalamic tracts, link each human retina with the SCN. Studies have since shown that the retino-hypothalamic tracts are critical pathways for the transmission of visual information required for proper functioning of the human circadian system in accordance with a twenty-four hour day.
In particular, it has been found in mammals that bilateral transection of the optic nerve interrupts both the retino-hypothalamic tract and the optic tract, leading to blindness and a complete loss of synchronization or entrainment of the circadian system to the twenty-four hour day. In contrast, entrainment is maintained after bilateral transection of the primary optic tract which leaves the retino-hypothalamic tract intact, but the animal behaviorally blind. Therefore, the retino-hypothalamic tract is a critical pathway for transmission of the visual information required for entrainment of the circadian cycle to a twenty-four hour day. In addition, the retino-hypothalamic tract is a critical pathway for transmission of visual information from the retina to the SCN and from the SCN to the pineal gland (see FIG. 2).
Information that is transmitted along this pathway includes the presence or absence of environmental light. It has been found that light, and the absence thereof, has an effect on the secretion of melatonin from the pineal gland in humans. It was demonstrated in studies by Lewy et al. that bright light applied to the human retina during the subjective night, when melatonin secretion (the timing of which is regulated by the SCN) is normally high, will suppress such secretion. "Light Suppresses Melatonin Secretion in Humans," Lewy et al., Science, Vol. 210. Dec. 12, 1980, pp. 1267-69. The ability to artificially suppress human melatonin secretion is an important indicator that light signals reach the circadian clock located in the SCN (i.e., that the subject possesses residual photic input). The ability to synchronize the human circadian pacemaker to the twenty-four hour light-dark cycle is contingent upon the proper functioning of the retino-hypothalamic tract of the human, which as noted above is the passageway for transmitting the presence of stimuli from the retina to the SCN.
Many chronic sleep disturbances are associated with abnormalities in the human circadian rhythms such as the core body temperature cycle and melatonin secretion. When these rhythms are entrained, the human is synchronized to a twenty-four hour daily cycle. On the other hand, when these rhythms are not synchronized, the human is likely to experience chronic sleep disturbances (e.g. insomnia). Czeisler et al. have previously described a method for synchronizing the human circadian pacemaker. Czeisler et al., "Light Resets the Human Circadian Pacemaker Independent of the Timing of the Sleep-Wake Cycle," Science 233:667-71 (Aug. 8, 1986). The method involves the application of light and dark stimuli to a subject at a predetermined time in order to shift a subject's normal rest-activity cycle to a desired cycle. The advantages to such a shift are numerous and include the ability to overcome jet lag, adjust to shift work, and to simply wake at a routine time without being groggy.
It has been discovered that a dysfunctioning retino-hypothalamic tract is unable to transmit the presence of stimuli to the brain in order to achieve synchronization or phase shifts of the circadian pacemaker in response to light. However, as noted above, a dysfunctioning primary optic tract (resulting in the inability to perceive light and dark) are not always indicative of a dysfunctioning retino-hypothalamic tract. Furthermore, damage to the occipital cortex (the region of the brain responsible for the conscious processing of visual information) or to the retina can also result in the inability of the subject to perceive light and dark, yet these dysfunctions are not always indicative of a dysfunctioning retino-hypothalamic tract. That is, a subject can be behaviorally blind (unable to perceive light and dark) and still have a functioning retino-hypothalamic tract. Preliminary tests by applicants have shown that a majority of blind humans suffer from disrupted sleep characterized by numerous nocturnal arousals and excessive daytime sleepiness. However, because of the perception that blind individuals are not responsive to light, it was believed that exposure to artificial or natural light stimuli had no effect on entrainment of the endogenous circadian pacemaker. Thus, preservation of residual visual input was not believed to be of importance to such subjectively "blind" patients and as a result, therapy such as dark glasses which reduce the input of light to the visual system are often used. Such behavior may worsen the occurrence of severe chronic sleep disturbances in blind humans. Similarly, aging is associated with a functional decrease in vision, possibly leading to a decreased input of photic information to the SCN. Diminishing ocular input to the SCN may be partly responsible for age-related changes in the circadian timing system.
Preliminary data suggests that preserving visual input in blind patients may be of great importance as even a residual input may be capable of keeping the circadian pacemaker in synchrony with the 24-hour day and thus preventing the onset of a severe and chronic sleep disorder. If the circadian pacemaker in some blind individuals is responsive to bright light pulses administered during the melatonin suppression test of the present invention, therapeutic trials to synchronize their biological clocks by critically timed bright light exposure could be considered. Further evaluation of blind patients who suffer from sleep disturbances will be possible along with suggestions regarding their living habits (e.g., to avoid wearing dark glasses or to spend time outdoors at certain times of day; to expose themselves to artifical bright light sources at critical times).
Thus, the need exists for a method of evaluating the functional integrity of the human visual system (including the photoreceptive elements, the retino-hypothalamic tract and its connections to the SCN) which mediates photic input from the retina to the hypothalamus, and in particular, the visual system of a behaviorally blind or visual impaired human being. Such an evaluation is especially helpful in determining if the visual system is sufficiently intact for entrainment of the circadian pacemaker.